Recent decades have seen an incredible growth in the prevalence of diabetes. The increasing frequency of this disorder threatens the health of our society and puts into focus the current lack of adequate prevention and treatment options. While it is important to pursue multiple therapeutic strategies, harnessing the regenerative capacity of islet -cells to increase an individual's insulin secretion capacity is among the promising approaches. Recently, discovery-oriented unbiased chemical screening led to the identification of the metabolic enzyme adenosine kinase (ADK) as a regulator of rodent and porcine -cell replication. Importantly, small molecule ADK-inhibitors selectively stimulate replication of -cels, but not alpha-cells, in vitro and in vivo. The identification of ADK as a regulator of -cell regeneration has raised several important questions. Does long-term inhibition of ADK in vivo promote -cell mass expansion and protect against developing diabetes? How does a broadly expressed metabolic enzyme selectively control the growth of a specific cell- type? Importantly, mature human -cells are resistant to growth stimuli. Presently, there is very limited understanding of why human -cells appear to be replication incompetent. This proposal describes a systematic approach to answering these critical questions and to uncovering the molecular basis of human - cell growth resistance. Complementary experimental strategies of genetic and chemical inhibition of ADK are employed to assess the in vivo impact of disrupting ADK function and to understand how ADKis promote -cell replication. Additionally, the ability of ADK inhibitors to promote rodent -cell replication and innovative transcriptomic-based strategies are leveraged to uncover why human -cells are refractory to growth stimuli. The long-term aim of this work is to uncover methods of stimulating mature human -cell regeneration.